The aims of this proposal are first, to develop a safe and effective cocaine antagonist, which when given to cocaine addicts, will abolish their craving for the drug and eliminate drug-seeking behavior. The second major aim of this proposal is to develop a heroin antagonist which can be used as a methodone replacement without the necessity of undergoing prior detoxification. These drugs should be long-acting, orally effective and have minimal or no abuse potential. Buprenorphine and naltrexone have been shown to decrease markedly cocaine abuse in human addicts (Kosten et al., Life Sci., 1989, 44, 887). Naltrexone, a pure opioid antagonist, will precipitate a severe withdrawal syndrome when given to heroin addicts, whereas buprenorphine, a mixed agonist-antagonist can be substituted for methadone, albeit with some discomfort to heroin addicts. Abrupt withdrawal from subjects maintained on 8 mg of buprenorphine produces a delayed but mild to moderate withdrawal syndrome for which the subjects demand drugs for relief. Since many cocaine addicts are heroin dependent, naltrexone is contraindicated in this population. We proposed to synthesize several examples in three chemically distinct groups of compounds which are putative mixed agonist-antagonists. These groups are: oripavines, 146-cinnamamidomorphinans and a new class of compounds, oxetanomorphinans. All target compounds will be tested at the medical college of Virginia and the Univ. of Michigan after submission to Dr. Arthur Jacobson (NIH).